Meningiomas are tumors arising from the arachnoidal cells of the meninges that may occur sporadically, or in association with the inherited disorder, neurofibromatosis 2 (NF2). They account for about 25% of brain tumors and cause significant morbidity. The familial tumors of NF2 are caused by inactivation of a 22q12 tumor suppressor gene while sporadic meningiomas can be divided into two groups: those that are mutated at the NF2 locus (-60%) and those that are not. As part of this Program Project grant, in 1993, we successfully isolated the NF2 gene, dubbing its novel tumor suppressor ?merlin?, due to a striking similarity to moesin, ezrin and radixin (ERM proteins) cytoskeleton-membrane linker proteins of the protein 4.1 family. Over the past grant period, we developed the reagents necessary to analyze merlin function and performed a basic characterization of merlin?s structure and expression. As virtually all germline and somatic NF2 mutations involve elimination of intact merlin protein, we now have a direct assay to classify primary meningioma specimens and to examine the activity of merlin in arachnoidal cells and their tumors. Consequently, over the next grant period, we intend to use molecular genetic strategies to further define the genetic causes of meningioma initiation and progression and to relate these to the function and regulation of merlin in arachnoidal cells and meningioma cells. Our underlying hypotheses are that merlin?s involvement with membrane remodeling is required for establishment of appropriate adhesion and cell contacts of arachnoidal cells and that meningiomas without NF2 mutation are due to inactivation of another gene that is also required for these functions. Meninigiomas and other NF2-related tumors offer a window on the genetic and biochemical mechanisms that produce benign tumors with significant medical impact. In this project we also aim to expand this window by using genetic linkage and tumor studies to discover genes that cause other inherited disorders phenotypically related to neurofibromatosis which also involve the formation of benign tumors. Overall, our studies should improve our understanding of the molecular biology behind slow-growing, benign tumors affecting the nervous system and provide clues for development of novel therapies.